Status of current pneumococcal vaccines. S. pneumoniae is a gram-positive encapsulated diplococcus. Capsule, a layer of polysaccharide (PS) surrounding the bacterial cell, is a major virulence factor of S. pneumoniae. Based on the differences in structure and immunological response to capsular polysaccharide, S. pneumoniae can be divided into more than 90 different serotypes. Capsular polysaccharides are the base for the currently used vaccines. The FDA has approved two types of pneumococcal vaccines for use in humans: a 23-valent PS vaccine and a 7-valent PS/protein conjugate vaccine. The former is comprised of capsular polysaccharide purified from 23 different serotypes of S. pneumoniae, which account for almost 89 percent of disease cases. PNEUMOVAX® (Merck) is an example of this group of vaccines. However, PS elicits type-specific antibodies. Antibodies raised for one serotype do not provide protection against infection of other serotypes. The efficacy of the 23-valent vaccine is limited. Furthermore, PS is a T-cell independent antigen which induces short-term immunity without immune memory and is not effective in children younger than two years of age (Greenwood B M et al., Trans R Soc Trop Med Hyg, 1980, 74:756-760). It is only recommended for high risk groups, such as the elderly and persons with underlying disease. A recently approved pneumococcal vaccine is a mixture of conjugates of 7 different individually prepared capsular polysaccharides covalently linked with carrier protein CRM197, which is a non-toxic and immunologically cross-reactive mutant of diphtheria toxin (Uchida et al, J. Biol. Chem. 248:3838-3844, 1973) and a component of the pediatric DPT (Diphtheria-Tetanus-Pertussis toxin) vaccine. Upon conjugation to a carrier protein, the otherwise T-cell independent PS becomes a T-cell dependent antigen by obtaining the immunological property of the protein. (Schneerson R et al., J Exp Med 1980, 152:361-376). The conjugate induces long-lasting immunity with immune memory and is effective in young infants. The 7 serotypes were selected for their prevalence in pediatric diseases. A conjugate vaccine of 7 pneumococcal capsular PS (PCV7) with CRM197 (Wyeth) is the only vaccine of this family that is commercially available. It is only prescribed for use in the prevention of pediatric invasive pneumococcal disease because of its high cost and limited supply. The drawback of these two families of vaccines is that they only provide protection against infection by the specific serotypes of S. pneumoniae that are included in the respective vaccine formulations.
Status of current meningococcal vaccine. N. meningitidis is a gram-negative, encapsulated diplococcus. At least 13 different serogroups have been identified based on the structure of capsular PS, but serogroups A, B, C, Y, and W-135 account for almost all cases of disease. Serogroup B organisms account for 46 percent of all cases, serogroup C for 45 percent of all cases, and serogroups W-135 and Y and strains that could not be serogrouped account for most of the remaining cases. Like S. pneumoniae, the major ingredient for meningococcal vaccines is capsular PS. Its vaccines can be divided into two families: the capsular PS vaccine and PS-protein conjugate vaccines. Three versions of PS vaccines are commercially available.
Quadrivalent PS vaccine (GlaxoSmithKline and Sanofi-Pasteur) is composed of capsular PS purified from serogroups A, C, Y, and W-135. It is expensive and not affordable for developing countries. Bivalent PS vaccine (GlaxoSmithKline and Sanofi-Pasteur) is composed of capsular PS purified from serogroups A and C. Trivalent PS vaccine (GlaxoSmithKline) is composed of capsular PS purified from serogroups A, C, and W-135. This vaccine has been used in the epidemics in the “Meningitis Belt” countries in Africa. Like pneumococcal vaccine, PS vaccine is not efficacious in children younger than two years of age. Such deficiency can be overcome by PS-protein conjugates.
Two types of meningococcal vaccine conjugates are commercially available or being developed. MENACTRA® (Sanofi-Pasteur) is the first quadrivalent conjugate meningococcal vaccine. It is a mixture of meningococcal polysaccharides (groups A, C, Y, and W135) conjugated with diphtheria toxoid. A monovalent meningococcal conjugate vaccine currently under development is a conjugate of serogroup C polysaccharide-diphtheria toxoid (Chiron and Wyeth), serogroup C PS-tetanus toxoid (Chiron, Baxter), and serogroup A PS-tetanus toxoid (PATH-SII). Preliminary results of clinical trials indicate these vaccines are efficacious.
With the burden of S. pneumoniae and N. meningitidis infection on the public health system at a global scale, it is desirable to have a single vaccine that is effective to prevent disease resulting from the infection of both pathogens.